Natural killer (NK) cells are thought to be an important aspect of the natural defense against viruses and tumors and may be required for normal hematopoeitic homeostasis. Although the effector cells that lyse HSV-1-infected fibroblasts [NK(HSV-FS)] are clearly NK cells, they differ from the cells that lyse the commonly used K562 tumor targets. This may be important since a deficiency of NK(HSV-FS) but not NK(K562) was associated with severe virus infections. In this work, we will investigate two aspects of the basic biology of NK(HSV-FS) effectors. First, we will further define heterogeneity of human NK. The NK(K562) effectors will be compared to those that lyse HSV-FS targets. In addition, effector cells that lyse HSV-1-infected lymphoblastoid cell lines will be compared to determine whether the target of virus infection rather than the virus itself determines which effector is active. These studies will include determination of cell-surface phenotype using monoclonal antibodies, single-cell binding and cytotoxicity assays, and limiting dilution cloning studies to look at the specificity of NK-cell clones. Second, we will determine why HSV-1 infection renders target cells more susceptible to lysis than uninfected cells. Several possibilities will be considered. Virus infection may make the infected target inherently less stable as detected by osmotic sensitivity and susceptibility to complement and T cell-mediated lysis. Possible differences in target binding cell numbers, cytotoxic activity, and recycling capacity will be measured in the single cell cytotoxicity and kinetics assays. The role of viral products, and especially viral glycoproteins, in conferring susceptibility of the infected cells to lysis will be examined. For these studies, viral mutants, virus-specific drugs, and monoclonal antibodies directed against HSV glycoproteins will be employed. Preferential induction or sensitivity to cytotoxic factors will also be tested. A better understanding of the basic biology of these NK effectors should facilitate the definition of their biological roles. (LB)